title: Drug interaction study between bupropion and ticlopidine in male CF-1 mice.
abstract: Bupropion is an atypical antidepressant that is biotransformed in humans to its major active metabolite hydroxybupropion by cytochrome P450 2B6 (CYP2B6). Co-administration of bupropion with an inhibitor of CYP2B6 can result in a serious drug interaction, leading to bupropion related adverse effects (e.g. seizures). The antiplatelet agent ticlopidine has been identified as a potent in vitro inhibitor of bupropion hydroxylation, however it is unknown if it interacts in vivo in rodents. In this study we investigated the potential pharmacokinetic (PK) drug interaction between bupropion and ticlopidine in mice. Using a destructive sampling design, male CF-1 mice were administered ticlopidine 1.0 mg/kg daily for 5 d, followed by single-dose bupropion 50 mg/kg. Bupropion and hydroxybupropion levels were measured by HPLC-UV in plasma and brain tissues at 30, 60, 90, 120 and 180 min post-dose, and compared between treatment groups. There was a strong trend in both plasma and brain data towards greater bupropion levels and smaller hydroxybupropion levels in ticlopidine treated mice. Analysis of variance indicated statistical differences (p<0.05) at many time points. The variance associated with the area under the curve was calculated using Bailer's method and significant differences were found between treatment groups. Taken together, the concentration time point statistical analysis followed by PK modeling demonstrate a significant PK drug interaction between bupropion and ticlopidine. To our knowledge, this is the first study to document an in vivo drug interaction between these drugs in mice. Our findings support future in vivo drug interaction studies in mice between bupropion and CYP2B6 inhibitors.
authors.affiliation: Department of Pharmaceutical, Biomedical and Administrative Sciences, College of Pharmacy and Health Sciences, Drake University, Des Moines, IA 50311, USA.
authors.forename: Jillissa Christine
authors.initials: JC
authors.lastname: Molnari
authors.forename: Hazem EmadEldin
authors.initials: HE
authors.lastname: Hassan
authors.forename: Bryant Michael
authors.initials: BM
authors.lastname: Moeller
authors.forename: Alan Lewis
authors.initials: AL
authors.lastname: Myers
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000378:metabolism*; D016642:Bupropion / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D065702:Cytochrome P-450 CYP2B6; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006900:Hydroxylation; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D013988:Ticlopidine / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D016642:Bupropion; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D013988:Ticlopidine